Functional dyspepsia (FD) and gastroparesis (GP) are upper gastrointestinal (GI) disorders that are collectively characterized by symptoms that include bloating, epigastric (upper abdominal) pain and/or burning, nausea, vomiting and early satiation. Therapeutic options for FD and GP patients are extremely limited, due to both lack of efficacy and poor safety profiles for existing therapies. Dyspepsia is defined as the presence of one or more dyspepsia symptoms (epigastric pain, burning, bothersome postprandial fullness, and early satiation) that are considered to originate from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms (see Drossman, D. A., ed., Rome III: The Functional Gastrointestinal Disorders, 3rd Ed., McLean, Va.: Degnon Associates, Inc., 2006). FD refers to dyspepsia that has no structural explanation after standard medical investigations, including upper endoscopy. Pathophysiological mechanisms that may be involved in FD include, among others, delayed gastric emptying, impaired gastric accommodation, hypersensitivity to gastric distention, altered duodenal sensitivity to lipids or acid, and abnormal duodenojejunal motility. Prolonged duodenal acid exposure is also seen in some FD and GP patients, and this exposure may slow gastric emptying and cause FD or GP-like symptoms. Dyspepsia is a common syndrome that accounts for about 30% of cases seen by gastroenterologists, with FD representing about 60% of all such dyspepsia cases.
GP refers to abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical obstruction. GP may be idiopathic or may be caused by various conditions, including Type I or Type II diabetes mellitus, viral infection, scleroderma, nervous system disorders such as Parkinson's disease, metabolic disorders such as hypothyroidism, post-operative ileus, and certain medications, including narcotic pain medications, tricyclic antidepressants and calcium channel blockers. Treatment for cancer, including chemotherapeutic drugs and radiation to the chest and abdomen can also cause gastroparesis, either temporarily or permanently. The most common symptoms are nausea, vomiting, bloating, epigastric pain, weight loss and early satiation. Gastroparesis is a chronic condition that can lead to frequent hospitalization, decreased quality of life, and increased disability and, in severe cases, increased mortality. Severe, symptomatic GP is common in individuals suffering from diabetes, affecting from 5-10% of diabetics for a total patient population of 1 million in the U.S. alone.
Constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation (CC) are common lower gastrointestinal (GI) disorders. IBS-C is characterized by symptoms that include recurrent abdominal pain or discomfort, fewer than three bowel movements per week, lumpy or hard stools, defecation straining, a feeling of incomplete bowel movement, passing mucus and/or bloating (Drossman et al., Rome III: The Functional Gastrointestinal Disorders, 3rd Ed., McLean, Va.: Degnon Assoc., Inc., 2006). Chronic constipation (also called functional constipation) is characterized by defecation straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, and/or fewer than three bowel movements per week (Drossman 2006).
Inflammatory bowel disease (IBD) refers to a group of gastrointestinal (GI) disorders characterized by active inflammation of the colon and/or small intestine. The main forms of IBD are ulcerative colitis (UC) and Crohn's disease but also include collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behçet's syndrome and infective colitis. UC is restricted to the colon and the rectum while Crohn's disease can affect the entire GI tract, although most cases affect the lower part of the GI tract, starting in the terminal ileum and affecting the lower small intestine, colon and rectum. In addition, UC is restricted to the epithelial lining of the gut, while Crohn's disease can affect the whole bowel wall. Both UC and Crohn's disease can cause abdominal pain and diarrhea and may increase the risk of colorectal cancer. It is estimated that up to one million people in the US are affected by IBD, with male and female patients appearing to be equally affected.
About 10% of Americans older than 40 and about half of all people older than 60 have diverticulosis, which is a condition in which small pouches in the lining of the colon bulge outward through weak spots. These pouches, called diverticula, are most common in the lower portion of the colon. About 10 to 25% of people with diverticulosis develop diverticulitis, which is an inflammation or infection of the diverticula. Symptoms of diverticulitis include abdominal pain, fever, nausea and a change in bowel habits, and complications include bleeding, bowel perforations and blockages in the colon.
Colorectal cancer, also called colon cancer or large bowel cancer, refers to cancerous growths in the colon and rectum. Colorectal cancer is the fourth most common form of cancer in the US and is responsible for 655,000 deaths worldwide per year. Although colorectal cancer may be cured if found before it has metastasized, it often is not diagnosed until there has been significant metastasis, because it may cause no symptoms. Uroguanylin and guanylin levels, which are the natural ligands of GC-C, are decreased or lost in colorectal cancer and activation of GC-C reverse the tumorigenic phenotype of colorectal cancer cells. Thus, it has been suggested that colon cancer may be treated or prevented with oral supplementation with GC-C agonists (Li et al., Curr. Mol. Pharmacol. 2:285-92, 2009). Conventional treatment options for FD and GP, IBS-C, CC, IBD, diverticulitis, colorectal cancer as well as other disorder have been of limited efficacy for many patients. Thus, there remains a need for new compounds and methods for treating these disorders.